OAS antiviral response (Homo sapiens)

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3, 201, 11, 14, 162, 810, 269, 27, 306, 13, 18, 1918, 24717, 3315344, 2828, 29263422, 25cytosolDengue virus dsRNA intermediate form ATPRNASEL:2'-5'oligoadenylateOAS1:OAS1 ligandOAS1 ligandTBEV dsRNA intermediate form PDE12PPiOAS3 RNASELABCE1:RNASELOAS1 tetramer:OAS1ligandRNASEL:FLNADengue virus dsRNA intermediate form OAS3 ligandWNV dsRNA intermediate form FLNA2'-5' oligoadenylateATPssRNATBEV dsRNA intermediate form PPiOAS2:OAS2 liganddimerRNA fragment with2'-3' cyclicphosphateAMPRSV dsRNAintermediate formRSV dsRNA intermediate form TBEV dsRNA intermediate form Sindbis virus dsRNA intermediate form DDX58OAS2 H+RNASEL Dengue virus dsRNA intermediate form 2'-5' oligoadenylate RNASEL H2OProtein VP3OAS3:OAS3 ligandFLNA OAS3OAS2 ABCE1OAS1 Influenza A dsRNA intermediate form OASLWNV dsRNA intermediate form ATPRSV dsRNA intermediate form FLUAV UpN-ssRNAATPOASL ABCE1 PPiDDX58 OAS2Dengue virus dsRNA intermediate form RNASEL Sindbis virus dsRNA intermediate form OAS1 OAS2:OAS2 ligandWNV dsRNA intermediate form Influenza A dsRNA intermediate form WNV dsRNA intermediate form Dengue virus dsRNA intermediate form OAS1OASL:DDX58WNV dsRNA intermediate form 1428, 31521, 23, 3251212


Description

The human oligoadenylate synthetase (OAS) family consists of four proteins whose production is stimulated by interferon, OAS1, OAS2, OAS3, and OASL. The first three members have the 2'-5'-oligoadenylate synthetase activity for which the family is named (Sadler AJ & Williams BR 2008), whereas OASL is devoid of this activity despite sharing significant sequence similarity with the other OAS proteins (Zhu J et al. 2015). OAS1, 2, and 3 are activated by double-stranded RNA to synthesize 5'-triphosphorylated 2'-5'-oligoadenylates (2-5A) from ATP (Kerr IM & Brown RE 1978). The 2-5A serve as chemically unique second messengers that induce regulated RNA decay by activating ribonuclease L (RNase L), thus mediating antiviral innate immunity (Zhou A et al. 1993; Lin RJ et al. 2009; Huang H et al. 2014; Han Y et al. 2014). RNase L has also been implicated in antibacterial innate immunity (Li XL et al. 2008). RNase L cleaves single-stranded RNA (ssRNA) in U-rich sequences, typically after UU or UA dinucleotides leaving a 5'-OH and 2',3'-cyclic phosphate (Floyd-Smith G et al. 1981; Wreschner DH et al.1981; Cooper DA et al. 2014).

Some OAS proteins have additional or alternative antiviral functions that are independent of RNase L activity (Perelygin AA et al., 2002; Kristiansen H et al. 2011). The precise mechanisms of RNase L-independent OAS antiviral activities remain to be fully elucidated. View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8983711
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Shamovsky, Veronica

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Bibliography

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  3. Tanaka N, Nakanishi M, Kusakabe Y, Goto Y, Kitade Y, Nakamura KT.; ''Molecular basis for recognition of 2',5'-linked oligoadenylates by the N-terminal ankyrin repeat domain of human ribonuclease L.''; PubMed Europe PMC
  4. Ibsen MS, Gad HH, Thavachelvam K, Boesen T, Desprès P, Hartmann R.; ''The 2'-5'-oligoadenylate synthetase 3 enzyme potently synthesizes the 2'-5'-oligoadenylates required for RNase L activation.''; PubMed Europe PMC
  5. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T.; ''The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.''; PubMed Europe PMC
  6. Sarkar SN, Bandyopadhyay S, Ghosh A, Sen GC.; ''Enzymatic characteristics of recombinant medium isozyme of 2'-5' oligoadenylate synthetase.''; PubMed Europe PMC
  7. Zhu J, Zhang Y, Ghosh A, Cuevas RA, Forero A, Dhar J, Ibsen MS, Schmid-Burgk JL, Schmidt T, Ganapathiraju MK, Fujita T, Hartmann R, Barik S, Hornung V, Coyne CB, Sarkar SN.; ''Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensor.''; PubMed Europe PMC
  8. Silverman RH, Weiss SR.; ''Viral phosphodiesterases that antagonize double-stranded RNA signaling to RNase L by degrading 2-5A.''; PubMed Europe PMC
  9. Martinand C, Montavon C, Salehzada T, Silhol M, Lebleu B, Bisbal C.; ''RNase L inhibitor is induced during human immunodeficiency virus type 1 infection and down regulates the 2-5A/RNase L pathway in human T cells.''; PubMed Europe PMC
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  11. Han Y, Whitney G, Donovan J, Korennykh A.; ''Innate immune messenger 2-5A tethers human RNase L into active high-order complexes.''; PubMed Europe PMC
  12. Son KN, Liang Z, Lipton HL.; ''Double-Stranded RNA Is Detected by Immunofluorescence Analysis in RNA and DNA Virus Infections, Including Those by Negative-Stranded RNA Viruses.''; PubMed Europe PMC
  13. Behera AK, Kumar M, Lockey RF, Mohapatra SS.; ''2'-5' Oligoadenylate synthetase plays a critical role in interferon-gamma inhibition of respiratory syncytial virus infection of human epithelial cells.''; PubMed Europe PMC
  14. Malathi K, Siddiqui MA, Dayal S, Naji M, Ezelle HJ, Zeng C, Zhou A, Hassel BA.; ''RNase L interacts with Filamin A to regulate actin dynamics and barrier function for viral entry.''; PubMed Europe PMC
  15. Cooper DA, Banerjee S, Chakrabarti A, García-Sastre A, Hesselberth JR, Silverman RH, Barton DJ.; ''RNase L targets distinct sites in influenza A virus RNAs.''; PubMed Europe PMC
  16. Ezelle HJ, Malathi K, Hassel BA.; ''The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate Response.''; PubMed Europe PMC
  17. Silverman RH, Skehel JJ, James TC, Wreschner DH, Kerr IM.; ''rRNA cleavage as an index of ppp(A2'p)nA activity in interferon-treated encephalomyocarditis virus-infected cells.''; PubMed Europe PMC
  18. Hovanessian AG, Svab J, Marié I, Robert N, Chamaret S, Laurent AG.; ''Characterization of 69- and 100-kDa forms of 2-5A-synthetase from interferon-treated human cells.''; PubMed Europe PMC
  19. Sarkar SN, Miyagi M, Crabb JW, Sen GC.; ''Identification of the substrate-binding sites of 2'-5'-oligoadenylate synthetase.''; PubMed Europe PMC
  20. Sadler AJ, Williams BR.; ''Interferon-inducible antiviral effectors.''; PubMed Europe PMC
  21. Barkhash AV, Perelygin AA, Babenko VN, Myasnikova NG, Pilipenko PI, Romaschenko AG, Voevoda MI, Brinton MA.; ''Variability in the 2'-5'-oligoadenylate synthetase gene cluster is associated with human predisposition to tick-borne encephalitis virus-induced disease.''; PubMed Europe PMC
  22. Wood ER, Bledsoe R, Chai J, Daka P, Deng H, Ding Y, Harris-Gurley S, Kryn LH, Nartey E, Nichols J, Nolte RT, Prabhu N, Rise C, Sheahan T, Shotwell JB, Smith D, Tai V, Taylor JD, Tomberlin G, Wang L, Wisely B, You S, Xia B, Dickson H.; ''The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors.''; PubMed Europe PMC
  23. Lim JK, Lisco A, McDermott DH, Huynh L, Ward JM, Johnson B, Johnson H, Pape J, Foster GA, Krysztof D, Follmann D, Stramer SL, Margolis LB, Murphy PM.; ''Genetic variation in OAS1 is a risk factor for initial infection with West Nile virus in man.''; PubMed Europe PMC
  24. Sarkar SN, Ghosh A, Wang HW, Sung SS, Sen GC.; ''The nature of the catalytic domain of 2'-5'-oligoadenylate synthetases.''; PubMed Europe PMC
  25. Kubota K, Nakahara K, Ohtsuka T, Yoshida S, Kawaguchi J, Fujita Y, Ozeki Y, Hara A, Yoshimura C, Furukawa H, Haruyama H, Ichikawa K, Yamashita M, Matsuoka T, Iijima Y.; ''Identification of 2'-phosphodiesterase, which plays a role in the 2-5A system regulated by interferon.''; PubMed Europe PMC
  26. Donovan J, Dufner M, Korennykh A.; ''Structural basis for cytosolic double-stranded RNA surveillance by human oligoadenylate synthetase 1.''; PubMed Europe PMC
  27. Bisbal C, Martinand C, Silhol M, Lebleu B, Salehzada T.; ''Cloning and characterization of a RNAse L inhibitor. A new component of the interferon-regulated 2-5A pathway.''; PubMed Europe PMC
  28. Li Y, Banerjee S, Wang Y, Goldstein SA, Dong B, Gaughan C, Silverman RH, Weiss SR.; ''Activation of RNase L is dependent on OAS3 expression during infection with diverse human viruses.''; PubMed Europe PMC
  29. Donovan J, Whitney G, Rath S, Korennykh A.; ''Structural mechanism of sensing long dsRNA via a noncatalytic domain in human oligoadenylate synthetase 3.''; PubMed Europe PMC
  30. Bisbal C, Salehzada T, Silhol M, Martinand C, Le Roy F, Lebleu B.; ''The 2-5A/RNase L pathway and inhibition by RNase L inhibitor (RLI).''; PubMed Europe PMC
  31. Lin RJ, Yu HP, Chang BL, Tang WC, Liao CL, Lin YL.; ''Distinct antiviral roles for human 2',5'-oligoadenylate synthetase family members against dengue virus infection.''; PubMed Europe PMC
  32. Alagarasu K, Honap T, Damle IM, Mulay AP, Shah PS, Cecilia D.; ''Polymorphisms in the oligoadenylate synthetase gene cluster and its association with clinical outcomes of dengue virus infection.''; PubMed Europe PMC
  33. Cooper DA, Jha BK, Silverman RH, Hesselberth JR, Barton DJ.; ''Ribonuclease L and metal-ion-independent endoribonuclease cleavage sites in host and viral RNAs.''; PubMed Europe PMC
  34. Ghosh A, Sarkar SN, Guo W, Bandyopadhyay S, Sen GC.; ''Enzymatic activity of 2'-5'-oligoadenylate synthetase is impaired by specific mutations that affect oligomerization of the protein.''; PubMed Europe PMC

History

CompareRevisionActionTimeUserComment
101665view13:46, 1 November 2018DeSlOntology Term : 'immune response pathway' added !
101661view11:51, 1 November 2018ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2'-5' oligoadenylate R-HSA-8983696 (Reactome)
2'-5' oligoadenylateR-HSA-8983696 (Reactome)
ABCE1 ProteinP61221 (Uniprot-TrEMBL)
ABCE1:RNASELComplexR-HSA-8985205 (Reactome)
ABCE1ProteinP61221 (Uniprot-TrEMBL)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
DDX58 ProteinO95786 (Uniprot-TrEMBL)
DDX58ProteinO95786 (Uniprot-TrEMBL)
Dengue virus dsRNA intermediate form R-DVI-8983654 (Reactome)
FLNA ProteinP21333 (Uniprot-TrEMBL)
FLNAProteinP21333 (Uniprot-TrEMBL)
FLUAV UpN-ssRNAR-FLU-9009966 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
Influenza A dsRNA intermediate form R-FLU-6790580 (Reactome)
OAS1 ProteinP00973 (Uniprot-TrEMBL)
OAS1 ligandComplexR-NUL-9037713 (Reactome)
OAS1 tetramer:OAS1 ligandComplexR-HSA-8983629 (Reactome)
OAS1:OAS1 ligandComplexR-HSA-8983690 (Reactome)
OAS1ProteinP00973 (Uniprot-TrEMBL)
OAS2 ProteinP29728 (Uniprot-TrEMBL)
OAS2:OAS2 ligand dimerComplexR-HSA-8985031 (Reactome)
OAS2:OAS2 ligandComplexR-HSA-8985050 (Reactome)
OAS2ProteinP29728 (Uniprot-TrEMBL)
OAS3 ProteinQ9Y6K5 (Uniprot-TrEMBL)
OAS3 ligandComplexR-NUL-8985076 (Reactome)
OAS3:OAS3 ligandComplexR-HSA-8985156 (Reactome)
OAS3ProteinQ9Y6K5 (Uniprot-TrEMBL)
OASL ProteinQ15646 (Uniprot-TrEMBL)
OASL:DDX58ComplexR-HSA-8985113 (Reactome)
OASLProteinQ15646 (Uniprot-TrEMBL)
PDE12ProteinQ6L8Q7 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
Protein VP3ProteinB1NKT1 (Uniprot-TrEMBL)
RNA fragment with

2'-3' cyclic

phosphate
R-ALL-9009945 (Reactome) RNASEL cleaves ssRNA to generate 5'-OH, 2'-3' cyclic phosphate RNA fragments
RNASEL ProteinQ05823 (Uniprot-TrEMBL)
RNASEL:2'-5' oligoadenylateComplexR-HSA-8985132 (Reactome)
RNASEL:FLNAComplexR-HSA-8985408 (Reactome)
RNASELProteinQ05823 (Uniprot-TrEMBL)
RSV dsRNA intermediate formR-RSY-8985053 (Reactome)
RSV dsRNA intermediate form R-RSY-8985053 (Reactome)
Sindbis virus dsRNA intermediate form R-SIV-8985032 (Reactome)
TBEV dsRNA intermediate form R-TEN-8983630 (Reactome)
WNV dsRNA intermediate form R-WNI-8983640 (Reactome)
ssRNAR-ALL-170292 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2'-5' oligoadenylateArrowR-HSA-8983680 (Reactome)
2'-5' oligoadenylateArrowR-HSA-8985091 (Reactome)
2'-5' oligoadenylateArrowR-HSA-8985104 (Reactome)
2'-5' oligoadenylateR-HSA-8985123 (Reactome)
2'-5' oligoadenylateR-HSA-9009950 (Reactome)
2'-5' oligoadenylateR-HSA-9615042 (Reactome)
ABCE1:RNASELArrowR-HSA-8985201 (Reactome)
ABCE1R-HSA-8985201 (Reactome)
ABCE1TBarR-HSA-8985123 (Reactome)
AMPArrowR-HSA-9009950 (Reactome)
AMPArrowR-HSA-9615042 (Reactome)
ATPArrowR-HSA-9009950 (Reactome)
ATPArrowR-HSA-9615042 (Reactome)
ATPR-HSA-8983680 (Reactome)
ATPR-HSA-8985091 (Reactome)
ATPR-HSA-8985104 (Reactome)
DDX58R-HSA-8985153 (Reactome)
FLNAArrowR-HSA-8985123 (Reactome)
FLUAV UpN-ssRNAR-HSA-9009941 (Reactome)
H+ArrowR-HSA-9009950 (Reactome)
H+ArrowR-HSA-9615042 (Reactome)
H2OR-HSA-9009950 (Reactome)
H2OR-HSA-9615042 (Reactome)
OAS1 ligandR-HSA-8983671 (Reactome)
OAS1 tetramer:OAS1 ligandArrowR-HSA-8983688 (Reactome)
OAS1 tetramer:OAS1 ligandmim-catalysisR-HSA-8983680 (Reactome)
OAS1:OAS1 ligandArrowR-HSA-8983671 (Reactome)
OAS1:OAS1 ligandR-HSA-8983688 (Reactome)
OAS1R-HSA-8983671 (Reactome)
OAS2:OAS2 ligand dimerArrowR-HSA-8985097 (Reactome)
OAS2:OAS2 ligand dimermim-catalysisR-HSA-8985104 (Reactome)
OAS2:OAS2 ligandArrowR-HSA-8985138 (Reactome)
OAS2:OAS2 ligandR-HSA-8985097 (Reactome)
OAS2R-HSA-8985138 (Reactome)
OAS3 ligandR-HSA-8985157 (Reactome)
OAS3:OAS3 ligandArrowR-HSA-8985157 (Reactome)
OAS3:OAS3 ligandmim-catalysisR-HSA-8985091 (Reactome)
OAS3R-HSA-8985157 (Reactome)
OASL:DDX58ArrowR-HSA-8985153 (Reactome)
OASLR-HSA-8985153 (Reactome)
PDE12TBarR-HSA-8985123 (Reactome)
PDE12mim-catalysisR-HSA-9009950 (Reactome)
PPiArrowR-HSA-8983680 (Reactome)
PPiArrowR-HSA-8985091 (Reactome)
PPiArrowR-HSA-8985104 (Reactome)
Protein VP3TBarR-HSA-8985123 (Reactome)
Protein VP3mim-catalysisR-HSA-9615042 (Reactome)
R-HSA-8983671 (Reactome) Human oligoadenylate synthetase 1 (OAS1) recognizes double-stranded RNA (dsRNA) typically produced by viral infections. The X-ray crystal structure of human OAS1 bound to a model 18-bp dsRNA duplex revealed that dsRNA binding allosterically drives a functionally essential structural reorganization within human OAS1 that narrows the adenosine triphosphate (ATP)-binding cleft and repositions a catalytic residue to complete its active site (Donovan J et al. 2013). Once stimulated by dsRNA, OAS1 uses ATP to synthesize a series of 5'-triphosphorylated 2'-5'-linked oligoadenylates containing 2 to greater than 5 adenylyl residues. The 5'-triphosphorylated 2'-5’-linked triadenylate (i.e., ppp5’A2’p5’A2’p5’A) is typically the most abundant active species (Kerr IM & Brown RE 1978).
R-HSA-8983680 (Reactome) Oligoadenylate synthetase 1 (OAS1) produces the second messenger 5’-triphosphorylated 2'-5'-oligoadenylate (2-5A), which limits viral propagation through the activation of the enzyme RNase L (reviewed by Silverman RH 2007; Hornung V et al. 2014). OAS1 produces 2-5A from ATP by transferring an AMP unit from the AMP donor substrate (ATP) to the 2′-hydroxyl group of an AMP acceptor substrate, ATP or a preformed 2-5A oligomer (Lohofener J et al. 2015). This produces a 2-5A dimer (ppp5'A(2'-5')A) or an elongated 2-5A oligomer (ppp5'A((2'-5')A)n), as well as one molecule of pyrophosphate (PPi) for each AMP residue added (Lohofener J et al. 2015). Structural studies showed that RNA-induced conformational rearrangement in OAS1 positions the active site residues D75, D77, and D148 compactly for coordination of two Mg2+ ions and for binding of ATP (Donovan J et al. 2013). The assembly of this critical active-site structure of OAS1 provides the gate that couples binding of dsRNA to the production and downstream functions of 2-5A, enabling OAS1 to function as a sensor of double-stranded RNA (dsRNA) (Donovan J et al. 2013).
R-HSA-8983688 (Reactome) The tetramerization of 2'-5'-oligoadenylate synthetase OAS1 is required for enzymatic activity (Ghosh A et al. 1997).
R-HSA-8985091 (Reactome) 2'-5'-oligoadenylate synthetase 3 (OAS3) is a template-independent nucleotidyl transferase that, once activated by double-stranded RNA in the cytosol, produces second messenger molecules 5'-triphosphorylated 2′,5′-linked oligoadenylates (2-5A). OAS3 was reported to produce preferentially dimeric 2-5A (Rebouillat D et al. 1999). However recent reports showed that OAS3 is able to synthesize 2',5'-oligoadenylates of sufficient length (the triadenylate and longer) to activate RNase L and thus limit viral propagation (Ibsen MS et al. 2014; Li Y et al. 2016).
R-HSA-8985097 (Reactome) Gel filtration experiments using extracts from IFN-treated human HeLa and Daudi cells showed that 2',5'-oligoadenylate (2-5A) synthetase (OAS2, p69) exists as a dimer of 160 kDa (Marie I et al. 1990). Biochemical and mutational studies demonstrated that dimerization of OAS2 protein is required for its enzyme activity (Sarkar SN et al. 1999). Further, photo affinity cross-linking and peptide mapping to study the substrate binding sites in OAS2 have suggested that OAS2 is active only as a dimer because it catalyzes the joining of the acceptor substrate bound to one subunit to the donor substrate bound to the other subunit (Sarkar SN et al. 2002).
R-HSA-8985104 (Reactome) 2'-5'-oligoadenylate synthetase 2 (OAS2) polymerizes ATP into 5'-triphosphorylated, 2'-5'-linked oligoadenylate (2-5A) (Hovanessian AG et al. 1988; Sarkar SN et al. 1999, 2002). 2-5A molecules are recognized by ribonuclease L (RNase L) (Han Y et al. 2014; Huang H et al. 2014). Activated RNase L cleaves viral and cellular RNA resulting in the inhibition of viral replication (Silverman RH 2007).
R-HSA-8985123 (Reactome) Ribonuclease L (RNASEL) gene encodes an ankyrin (ANK) repeat domain containing dual endoribonuclease-pseudokinase RNase L that functions in the interferon (IFN) antiviral response (Wreschner DH et al. 1982; Zhou A et al.1993; Hassel BA et al. 1993; Huang H et al. 2014; Han Y et al. 2014). Upon activation by viral double-stranded RNA, 5'-triphosphorylated 2'-5'-linked oligoadenylates (2-5A) are synthesized by one of several 2'-5' oligoadenylate synthetases (OAS). The 2-5A binds to monomeric, inactive RNase L causing it to dimerize through the ANK domains (Dong B & Silverman RH 1995; Tanaka N et al. 2004, 2005; Han Y et al., 2012). Activated RNase L cleaves single-stranded viral and cellular RNA, predominantly after UpU and UpA dinucleotides (Floyd-Smith G et al. 1981; Wreschner DH et al. 1981). The triadenylate form of 2-5A is the minimal active molecule, however, longer 2',5'-oligoadenylates retain the ability to activate RNase L (Dong B et al. 1994).

RNase L possesses nine ankyrin repeats (the 9th being incomplete) in the N-terminus, and pseudokinase and nuclease domains in the C-terminus, which is also termed the kinase-extension nuclease (KEN) domain (Hassel BA et al. 1993; Tanaka N et al. 2004; Han Y et al. 2014; Huang H et al. 2014). The monomeric RNase L lacks nucleolytic activity, however, deletion of ankyrin repeats caused constitutive, albeit reduced, ribonuclease activity (Dong B et al. 1997). Crystal structure data indicate that 2-5A binds to the second and fourth ankyrin repeats and the pseudokinase domain (Tanaka N et al. 2004; Huang H et al. 2014; Han Y et al. 2014). These interactions, in conjunction with binding between the pseudokinase domains of the two protomers, mediate dimerization and enzymatic activation within minutes (Huang H et al. 2014; Han Y et al. 2012, 2014). Once active, RNase L cleaves ssRNA, including cellular mRNA and rRNA as well as microbial RNAs. In uninfected cells RNase L interacts with the actin-binding protein filamin A (FLNA) to modulate the actin cytoskeleton and inhibit virus entry into cells (Malathi K et al. 2014; Ezelle HJ et al. 2016). Upon infection and activation of its enzymatic activity by 2-5A, RNase L dissociates from FLNA to mediate its antiviral signaling (Malathi K et al. 2014; Ezelle HJ et al. 2016).

R-HSA-8985138 (Reactome) The human oligoadenylate synthetase 2 (OAS2) is activated by double-stranded RNA (dsRNA) (Hovanessian AG et al. 1988; Behera AK et al. 2002; Kristiansen H et al. 2011).
R-HSA-8985153 (Reactome) Interferon-dependent antiviral mechanisms trigger activation of 5'-triphosphorylated 2'-5'oligoadenylate synthetase (OAS) proteins which bind double-stranded RNA and catalyze the synthesis of 5'-triphosphorylated 2'-5' oligoadenylates from ATP (Kristiansen et al. 2011). The p59 protein encoded by the OAS-like (OASL) gene is an atypical member of the OAS family in the sense that it lacks the characteristic 2'-5' oligoadenylate synthetase activity (Hartmann et al. 1998; Rebouillat et al. 1998). Furthermore, OASL contains two tandem ubiquitin-like domains (UBL) in the C-terminus, which are absent in other OAS proteins (Hartmann et al. 1998; Rebouillat et al. 1998). OASL is rapidly induced by virus infection via interferon regulatory factor 3 (IRF3) as well as by IFN signaling and has been shown to have antiviral activities, which requires the UBL domain (Melchjorsen et al. 2009; Sarkar and Sen 2004; Marques et al. 2008; Schoggins et al. 2011). OASL is thought to interact with and enhance RIG1 (DDX58) signaling through its C-terminal ubiquitin-like domain (UBL) by mimicking polyubiquitin (Zhu J et al. 2014). Loss of OASL expression reduced DDX58 signaling and enhanced virus replication in human cells. Conversely, OASL expression suppressed replication of a number of viruses in a DDX58-dependent manner and enhanced DDX58-mediated IFN induction (Zhu J et al. 2014).
R-HSA-8985157 (Reactome) Viral dsRNA-activated oligoadenylate synthetase 3 (OAS3) exhibits a strong preference for long dsRNA. A study that included the crystal structure of the N-terminal enzymatically inactive 2'-5' oligoadenylate synthetase domain of human OAS3 (hOAS3.DI) in complex with 19-bp dsRNA indicated that this domain I (DI) subunit has high affinity for the binding of long (>50 bp) dsRNA, which then is presented to the enzymatically active C-terminal domain III (DIII) of OAS3 that produces 5’-triphosphorylated 2'-5' olgoadenylates from ATP (Donovan J et al. 2015). OAS3 was reported to be the major antiviral human OAS isoform (Li Y et al. 2016).
R-HSA-8985201 (Reactome) ATP-binding cassette sub-family E member 1 (ABCE1, aka RNase L inhibitor, RLI) is a member of the ATP-binding cassette transporters which express in the cytoplasm and the nuclear membrane. ABCE1 is induced during viral infections (Bisbal C et al. 1995; Martinand C et al. 1998, 1999). ABCE1 (RLI) was shown to associate with RNase L inhibiting the endoribonuclease activity of RNase L, thus antagonising the anti-viral effect of the IFN-regulated 2'-5' oligoadenylate/RNase L pathway (Bisbal C et al. 1995; Martinand C et al. 1998, 1999). Furthermore, overexpression or knockdown of ABCE1 (RLI) has inhibitory or promoting effects on the binding of RNase L to 2'-5' oligoadenylates, rRNA cleavage, destabilization of mitochondrial mRNA, antiviral activity, and antitumor activity (Martinand C et al. 1998, 1999; Le Roy F et al. 2001; Malathi K et al. 2004; Huang B et al. 2014; Tian Y et al. 2016). Aside from its role as an RNase-L inhibitor, ABCE1 is believed to be involved in translation termination and ribosome recycling (Dong J et al. 2004; Chen ZQ et al. 2006; Khoshnevis S et al. 2010).
R-HSA-9009936 (Reactome) Ribonuclease L (RNase L) is an ankyrin (ANK) repeat domain containing dual endoribonuclease-pseudokinase which is encoded by RNASEL gene (Wreschner DH et al. 1982; Zhou A et al.1993; Hassel BA et al. 1993; Huang H et al. 2014; Han Y et al. 2014). Activated RNase L forms a homodimer (Dong B & Silverman RH 1995) which cleaves within single-stranded regions of different RNA substrates, predominantly after UpAp and UpUp dinucleotides, leaving 2',3'-cyclic phosphoryl and 5'-hydroxyl groups at the termini of the RNA cleavage products (Wreschner DH et al. 1981; Floyd-Smith G et al. 1981; Han Y et al. 2012; Cooper DA et al. 2014). The antiviral function of RNase L extends beyond direct cleavage of viral RNA and includes also cleavage of cellular RNA such as mRNA and rRNA that is required for viral replication (Wreschner DH et al. 1981; Silverman RH et al.1983; Brennan-Laun SE et al. 2014; Cooper DA et al. 2014). RNase L induces apoptosis to eliminate virus-infected cells and autophagy to limit viral infections in some circumstances (Zhou A et al. 1997; Castelli JC et al. 1997; Chakrabarti A et al. 2012). Depending on the cell type and basal levels of RNase L, viral and cellular RNA cleavage products induce signaling to the IFN beta gene through RIG-I and/or MDA5 and MAVS (Malathi K et al. 2007; Banerjee S etl al. 2014).
R-HSA-9009941 (Reactome) Ribonuclease L (RNase L) is an ankyrin (ANK) repeat domain containing dual endoribonuclease-pseudokinase which is encoded by RNASEL gene (Wreschner DH et al. 1982; Zhou A et al.1993; Hassel BA et al. 1993; Huang H et al. 2014; Han Y et al. 2014). Activated RNase L forms a homodimer (Dong B & Silverman RH 1995) which cleaves within single-stranded regions of different RNA substrates, predominantly after UpAp and UpUp dinucleotides, leaving 2',3'-cyclic phosphoryl and 5'-hydroxyl groups at the termini of the RNA cleavage products (Wreschner DH et al. 1981; Floyd-Smith G et al. 1981; Han Y et al. 2012; Cooper DA et al. 2014). The antiviral effect of RNase L occurs through a combination of effects and depends on the virus and cell type. This includes cleavage of viral genomic ssRNA that prevents viral replication (Cooper DA et al. 2015), cleavage of viral mRNA that inhibits viral protein synthesis, and cleavage of cellular RNA such as mRNA and rRNA that is required for viral replication (Wreschner DH et al. 1981; Silverman RH et al.1983; Brennan-Laun SE et al. 2014; Cooper DA et al. 2014). RNase L induces apoptosis to eliminate virus-infected cells and autophagy to limit viral infections in some circumstances (Zhou A et al. 1997; Castelli JC et al. 1997; Chakrabarti A et al. 2012). Depending on the cell type and basal levels of RNase L, viral and cellular RNA cleavage products induce signaling to the IFN beta gene through RIG-I and/or MDA5 and MAVS (Malathi K et al. 2007; Banerjee S et al. 2014).
R-HSA-9009950 (Reactome) Viral infection produces dsRNA that activates OAS isozymes to synthesize 5'-triphosphorylated 2'-5'-linked oligoadenylate (2-5A). Latent ribonuclease L (RNase L) binds 2-5A and oligomerizes into an active complex capable of cleaving ssRNA into retinoic acid-inducible gene-I (RIG-I) and nucleotide-binding oligomerizationdomain-like domain like receptor 3 (NLRP3) inflammasome-activating small RNAs (Malathi K et al. 2007; Chakrabarti A et al. 2015). Activation of RNase L can be attenuated by 2′-phosphodiesterase (PDE12)- mediated degradation of 2-5A. PDE12 is an endonuclease/exonuclease/phosphatase family member of deadenylases with both 3’,5’- and 2’,5’-phosphodiesterase activities. PDE12 localizes to the mitochondrial matrix and, in addition to degrading 2-5A, removes poly(A) tails from some mitochondrial mRNAs (Kubota K et al. 2004; Poulsen JB et al. 2011; Rorbach J et al. 2011; Silverman RH & Weiss SR 2014; Wood ER et al. 2015). The 2H phosphoesterase, AKAP7, is an unrelated nuclear enzyme that also degrades 2-5A (Gusho E et al. 2014). Several viruses, including some coronaviruses and rotaviruses, encode structurally related 2H phosphoesterases (each with two conserved histidine motifs) that degrade 2-5A and antagonize RNase L mediated antiviral activity (Zhao L et al. 2012; Zhang R et al. 2013; Silverman RH & Weiss SR 2014; Ogden KM et al. 2015; Sui B et al. 2016; Thornbrough JM et al. 2016; Goldstein SA et al. 2017).
R-HSA-9615042 (Reactome) Viral infection produces dsRNA that activates the 2'-5' oligoadenylate synthetase (OAS) to synthesize 5'-triphosphorylated 2'-5'-linked oligoadenylate from ATP. The 2'-5'-linked oligoadenylate with a chemical structure of ppp5'A(2'p5'A)n contain 2 to greater than 5 adenylyl residues (n>2) and are commonly referred to as 2-5A (Kerr IM & Brown RE 1978). The 2-5As bind latent ribonuclease L (RNase L) which in human is encoded by RNASEL gene. RNase L oligomerizes into an active complex capable of cleaving viral ssRNA and cellular ssRNA to inhibit viral replication and spread (Silverman RH 2007; Malathi K et al. 2007; Chakrabarti A et al. 2015). Viruses have developed diverse strategies to escape the host antiviral effects. Several viruses, including some coronaviruses and rotaviruses, encode structurally related 2H phosphoesterases with two conserved His-x-Ser/Thr motifs in their catalytic sites. The NS4b protein of Middle East respiratory syndrome coronavirus (MERS-CoV), the protein VP3 of rotavirus A (RVA), the non-structural 2 (NS2) protein of human respiratory coronavirus HCoV-OC43 and its homologue ns2 protein of mouse hepatitis virus (MHV) possess enzymatic 2′,5-phosphodiesterase (PDE) activity that is capable of antagonizing RNase L and thus countering a potent host antiviral response in mammals (Mazumder R et al., 2002; Zhao L et al. 2012; Zhang R et al. 2013; Silverman RH & Weiss SR 2014; Ogden KM et al. 2015; Sui B et al. 2016; Thornbrough JM et al. 2016; Goldstein SA et al. 2017). The viral 2',5'-PDEs are phylogenetically related to the cellular 2',5'-PDE, a kinase anchoring protein 7 (AKAP7) (Mazumder R et al., 2002; Gold MG et al. 2008; Ogden KM et al. 2015; Brandmann T & Jinek M 2015). Murine AKAP7 was found to cleave the phosphodiester bonds of 2-5A in vitro with rates similar to its viral homologues, ns2 of MHV and VP3 of RVA (Gusho E et al. 2014). Murine AKAP7 (full length and central domain) also effectively degraded 2-5A in intact pIC-transfected human ovarian carcinoma Hey1B cells (Gusho E et al. 2014). The proviral effect of murine AKAP7 required cytoplasmic localization of the PDE domain of AKAP7, whereas full-length AKAP7 was observed only in nuclei. Further studies are needed to identify the subcellular compartment of 2′,5′-PDE activity of AKAP7.

The Reactome event shows a cleavage of 2-5A by RVA protein VP3 as an example of viral 2',5'-PDE activity that antagonizes dsRNA signaling to RNase L.

RNA fragment with

2'-3' cyclic

phosphate
ArrowR-HSA-9009936 (Reactome)
RNA fragment with

2'-3' cyclic

phosphate
ArrowR-HSA-9009941 (Reactome)
RNASEL:2'-5' oligoadenylateArrowR-HSA-8985123 (Reactome)
RNASEL:2'-5' oligoadenylatemim-catalysisR-HSA-9009936 (Reactome)
RNASEL:2'-5' oligoadenylatemim-catalysisR-HSA-9009941 (Reactome)
RNASEL:FLNAR-HSA-8985123 (Reactome)
RNASELR-HSA-8985201 (Reactome)
RSV dsRNA intermediate formR-HSA-8985138 (Reactome)
ssRNAR-HSA-9009936 (Reactome)

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